Uptake Of Dietary Fatty Acids Research Articles

Adipocyte hypertrophy associates with in vivo postprandial fatty acid metabolism and adipose single-cell transcriptional dynamics

Adipocyte hypertrophy is associated with metabolic complications independent of obesity. We aimed to determine: 1) the association between adipocyte size and postprandial fatty acid metabolism; 2) the potential mechanisms driving the obesity-independent, hypertrophy-associated dysmetabolism invivo and at a single-cell resolution. Tracers with positron emission tomography were used to measure fatty acid metabolism in 40 men and women with normal or impaired glucose tolerance (NCT02808182), and single nuclei RNA-sequencing (snRNA-seq) to determine transcriptional dynamics of subcutaneous adipose tissue (AT) between individuals with AT hypertrophy vs. hyperplasia matched for sex, ethnicity, glucose-tolerance status, BMI, total and percent body fat, and waist circumference. Adipocyte size was associated with high postprandial total cardiac fatty acid uptake and higher visceral AT dietary fatty acid uptake, but lower lean tissue dietary fatty acid uptake. We found major shifts in cell transcriptomal dynamics with AT hypertrophy that were consistent with invivo metabolic changes.

Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease.

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing rapidly worldwide, and NASH has become a serious problem for human health. Recently, the selective activation of the intestinal farnesoid X receptor (FXR) was considered as a more promising strategy for the treatment of NASH with lesser side effects due to reduced systemic exposure. Moreover, the inhibition of intestinal fatty acid binding protein 1 (FABP1) alleviated obesity and NASH by reducing dietary fatty acid uptake. In this study, the first-in-class intestinal restricted FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive multiparameter optimization studies. The reduced systemic exposure of ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. With the above attractive efficacy and preliminary safety profiles, ZLY28 is worthy of further evaluation as a novel anti-NASH agent.

Total Postprandial Hepatic Nonesterified and Dietary Fatty Acid Uptake Is Increased and Insufficiently Curbed by Adipose Tissue Fatty Acid Trapping in Prediabetes With Overweight.

Excessive lean tissue uptake of fatty acids (FAs) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased nonesterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. In this study, 20 individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]palmitate. Hepatic (97 [range 36-215] mmol/6 h vs. 68 [23-132] mmol/6 h, P = 0.03) but not cardiac (11 [range 4-24] mmol/6 h vs. 8 [3-20] mmol/6 h, P = 0.09) uptake of most sources of postprandial FA (NEFA + DFA uptake) integrated over 6 h was higher in IGT versus NGT. DFA accounted for lower fractions of total cardiac (21% [5-47] vs. 25% [9-39], P = 0.08) and hepatic (19% [6-52] vs. 28% [14-50], P = 0.04) uptake in IGT versus NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake and was associated with higher total cardiac FA uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182).

Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis.

Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH. Intestinal PPARα was activated and fatty acid-binding protein 1 (FABP1) up-regulated in humans with obesity and high-fat diet (HFD)-fed mice as revealed by using human intestine specimens or HFD/high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed C57BL/6N mice and PPARA -humanized, peroxisome proliferator response element-luciferase mice. Intestine-specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity-associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with fatty acid uptake assays in primary intestinal organoids revealed that intestinal PPARα induced the expression of FABP1 that in turn mediated the effects of intestinal PPARα in modulating fatty acid uptake. The PPARα antagonist GW6471 improved obesity and NASH, dependent on intestinal PPARα or FABP1. Double-knockout ( Ppara/Fabp1ΔIE ) mice demonstrated that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally, GW6471 reduced human PPARA-driven intestinal fatty acid uptake and improved obesity-related metabolic dysfunctions in PPARA -humanized, but not Ppara -null, mice. Intestinal PPARα signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.

Contrasting Effects of Fasting on Liver-Adipose Axis in Alcohol-Associated and Non-alcoholic Fatty Liver.

Background: Fatty liver, a major health problem worldwide, is the earliest pathological change in the progression of alcohol-associated (AFL) and non-alcoholic fatty liver disease (NAFL). Though the causes of AFL and NAFL differ, both share similar histological and some common pathophysiological characteristics. In this study, we sought to examine mechanisms responsible for lipid dynamics in liver and adipose tissue in the setting of AFL and NAFL in response to 48 h of fasting.Methods: Male rats were fed Lieber-DeCarli liquid control or alcohol-containing diet (AFL model), chow or high-fat pellet diet (NAFL model). After 6–8 weeks of feeding, half of the rats from each group were fasted for 48 h while the other half remained on their respective diets. Following sacrifice, blood, adipose, and the liver were collected for analysis.Results: Though rats fed AFL and NAFL diets both showed fatty liver, the physiological mechanisms involved in the development of each was different. Here, we show that increased hepatic de novo fatty acid synthesis, increased uptake of adipose-derived free fatty acids, and impaired triglyceride breakdown contribute to the development of AFL. In the case of NAFL, however, increased dietary fatty acid uptake is the major contributor to hepatic steatosis. Likewise, the response to starvation in the two fatty liver disease models also varied. While there was a decrease in hepatic steatosis after fasting in ethanol-fed rats, the control, chow and high-fat diet-fed rats showed higher levels of hepatic steatosis than pair-fed counterparts. This diverse response was a result of increased adipose lipolysis in all experimental groups except fasted ethanol-fed rats.Conclusion: Even though AFL and NAFL are nearly histologically indistinguishable, the physiological mechanisms that cause hepatic fat accumulation are different as are their responses to starvation.

Obesity and Non-Alcoholic Fatty Liver Disease: Pathophysiology and Management Focused

The continuing rise of obesity epidemic in the global population has been markedly associated with the escalating occurrence and severity of non-alcoholic fatty liver disease (NAFLD). This condition represents a complex metabolic imbalance, primarily characterized by excessive intrahepatic accumulation of triglycerides, known as hepatic steatosis. This pathophysiological process is initiated by the disproportionation between the uptake of dietary fatty acids in plasma, as well as the increase of de novo fatty acid synthesis, which is not equally accompanied by the exportation and oxidation of fatty acid in the form of triglycerides. As mentioned earlier, the underlying metabolic process becomes a significant risk factor for developing cardiometabolic complications, involving type 2 diabetes mellitus, insulin resistance, and dyslipidemia. This review presents a comprehensive understanding of the pathogenesis and pathophysiology of obesity and NAFLD to determine innovative management approaches for the prevention and treatment of the disease.

Abstract 14088: Pro-neurotensin/neuromedin N is Associated With Incident Metabolic Syndrome

Introduction: The tridecapeptide neurotensin increases dietary fatty acid uptake and is implicated in insulin resistance in animal models and—through plasma levels of its stable precursor pro-neurotensin/neuromedin N (pro-NT/NMN)—with human diabetes mellitus, obesity, and cardiovascular disease. We evaluated the association of pro-NT/NMN with incident metabolic syndrome (MetS). Methods: This analysis included a subcohort of 2,770 Black and White participants without prevalent MetS at baseline (2003-2007) from the REasons for Geographic And Racial Differences in Stroke study who had fasting plasma pro-NT/NMN measured by immunoassay and completed a second assessment from 2013-2016. Incident MetS was defined as ≥3 harmonized criteria at follow-up: impaired glycemic control, high systolic blood pressure, high triglycerides, low high-density lipoprotein (HDL), and increased waist circumference. Four sequential weighted logistic regression models were fitted to incident MetS overall and for each criterion separately, incorporating demographic factors, metabolic risk factors, HOMA-IR, and diet scores. Results: Over mean 9.4 (standard deviation [SD] 1.0) years follow up, 564 participants developed MetS. Median [IQR] plasma pro-NT/NMN was 160 [118-218] pmol/L. In the overall group, higher log pro-NT/NMN was associated with incidence of lower HDL (odds ratio [OR] per SD pro-NT/NMN 1.16, 95% confidence interval [CI] 1.00-1.35) and impaired glycemic control (1.25, 95% CI 1.11-1.40), but not other MetS components. Each SD higher log pro-NT/NMN was associated with a 22% increased odds of incident MetS, adjusted for demographics (Table); this was not significant when controlling for HOMA-IR in all but the White subgroup (race p -interaction 0.05). No differences by sex were observed. Conclusions: Higher neurotensin likely augments insulin resistance to increase odds of incident metabolic syndrome through impaired glycemic control and lower HDL.

Multivariate factor analysis of milk fatty acid composition in relation to the somatic cell count of single udder quarters

The present study investigated whether the fatty acid composition of milk changes in relation to an increase in the milk somatic cell count (SCC) of separate udder quarters. We investigated the potential of multivariate factor analysis to extract metabolic evidence from data on the quantity and quality of milk of quarters characterized by different SCC levels. We collected data from individual milk samples taken from single quarters of 49 Italian Holstein cows from the same dairy farm. Factor analysis was carried out on 64 individual fatty acids. In line with a previous study on multivariate factor analysis, a variable was considered to be associated with a specific factor if the absolute value of its correlation with the factor was ≥0.60. Seven factors were extracted that explained the following groups of fatty acids or functions: de novo synthesis, energy balance, uptake of dietary fatty acids, biohydrogenation, short-chain fatty acids, very long chain fatty acids, and odd- and branched-chain fatty acids. An ANOVA of factor scores highlighted the significant effects of the SCC level on de novo fatty acids and biohydrogenation. The de novo fatty acid factor decreased significantly with a high level of SCC, from just 10,000 cells/mL, whereas the biohydrogenation factor showed a significantly higher level in quarters with SCC levels greater than 400,000 cells/mL. This statistical approach enabled us to reduce the number of variables to a few latent factors with biological significance and to represent groups of fatty acids with a common origin and function. Multivariate factor analysis could therefore be key to studying the influence of SCC on the lipid metabolism of single quarters. This approach also demonstrated the metabolic differences between quarters of the same animal showing a different level of SCC.

Bioinformatics analysis and tissue-specific expression of intestinal-type fatty acid binding protein in domestic pigeons (Columba livia)

ABSTRACT Intestinal fatty-acid binding protein (I-FABP, also called FABP2) is involved in the uptake of dietary fatty acids in the intestine, and its binding specificity is only with long-chain fatty acid. In this study, sequences of 4 exons in pigeon FABP2 were successfully amplified. The encoded protein had a molecular weight of 15.13 kDa and the theoretical pI was 6.75. Bioinformatics analysis indicated that the protein was predicted to contain 10 potential phosphorylation sites and did not contain signal peptide structure. The evolutionary analysis suggested the amino acid sequence of pigeon FABP2 was closest to the mallard (Nippoia nippon) homologs. Meanwhile the expression of FABP2 mRNA in different ages and tissues we conducted. It showed that the expression of the FABP2 gene was the highest in the liver, followed by the small intestine and adipose tissue, while lowest in the breast muscle. Also, the expression level in the gizzard was gradually increased with aging. Our results may serve as reference to better studies of the functional characterization and structure of the FABP2 in pigeon.

Cloning of fatty acid-binding protein 2 (fabp2) in loach (Misgurnus anguillicaudatus) and its expression in response to dietary oxidized fish oil.

Fatty acid-binding protein 2 (FABP2) is involved in the uptake of dietary fatty acids and intracellular fatty acid transport. In the present study, cDNA of fabp2 in loach (Misgurnus anguillicaudatus) was cloned and its full length was 956 bp, encoding 134 amino acids. Gene expression of fabp2 was investigated in different development stages and different tissues of loach, showing that the expression of fabp2 was recorded at 2 days after hatching (DAH), 10DAH, 20DAH and 35DAH, and higher in loach intestine, muscle and brain, compared with other tissues. We also investigated the effects of dietary oxidized fish oil (OFO) on the expression of intestinal fabp2 in loach juveniles by using fluorescence in situ hybridization (FISH) and real-time quantitative PCR. Fabp2 gene was expressed mainly by the intestinal epithelium cells of loach juveniles. The expression of intestinal fabp2 in loaches fed with OFO diet was significantly up-regulated on day 1 and 3, and down-regulated on day 10 after feeding, compared with those loaches fed with dietary fresh fish oil (FO), which were in accordance with the fluorescence intensities of FISH exhibiting in the corresponding feeding time. The present study indicated that dietary oxidized fish oil could affect the expression of fabp2 in the loach. Our results serve as reference to better understand the functional characterization of fabp2 in loach and other fish species.

Early Effects of Sleeve Gastrectomy (SG) on Systemic and Organ-Specific Dietary Fatty Acid Uptake, Postprandial Free Fatty Acids (FFA), and Glucose Metabolism in Type 2 Diabetes (T2D)

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve days after SG, whole body and hepatic insulin sensitivity increased significantly whereas fasting and postprandial EGP decreased. Postprandial GLP-1, GIP, PYY and glucagon were higher after vs. before SG. Postprandial AUC of FFA (175 vs. 228 mmol/Lx min; p< 0.05) and total FA oxidation were higher (p< 0.02 from 180 min to 360 min), but dietary FA oxidation was reduced after SG (p< 0.002 from 180 min to 360 min). After SG, uptake of dietary FA 6 hours after the meal was reduced in the myocardium (mean SUV 2.07± 0.66 vs. 1.36± 0.44; p=0.06) and was increased in visceral AT (mean SUV 0.24± 0.2 vs. 0.42± 0.2; p=0.03), without changes in other organs. In conclusion, there is reduced myocardial and increased visceral AT uptake of dietary FA associated with reduced dietary FA oxidation and increased FFA mobilization and oxidation, concomitant with reduced EGP and insulin sensitization in patients with T2D early after SG. Disclosure A. Carreau: None. C. Noll: None. B. Guerin: None. L. Biertho: Advisory Panel; Self; Novo Nordisk Inc.. Consultant; Self; Johnson & Johnson Services, Inc., Valeant Pharmaceuticals International, Inc.. E.E. Turcotte: None. A. Tchernof: Research Support; Self; Johnson & Johnson Services, Inc., Medtronic. A. Carpentier: Consultant; Self; UniQure, Janssen Pharmaceuticals, Inc., Siemens. Research Support; Self; Caprion, Merck Sharp & Dohme Corp., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, AstraZeneca, Bristol-Myers Squibb Company, Sanofi-Aventis, Pfizer Inc., Novo Nordisk Inc., Exelixis, Amgen Inc..

Cholecystokinin is involved in triglyceride fatty acid uptake by rat adipose tissue.

The incorporation of plasma triglyceride (TG) fatty acids to white adipose tissue (WAT) depends on lipoprotein lipase (LPL), which is regulated by angiopoietin-like protein-4 (ANGPTL-4), an unfolding molecular chaperone that converts active LPL dimers into inactive monomers. The production of ANGPTL-4 is promoted by fasting and repressed by feeding. We hypothesized that the postprandial hormone cholecystokinin (CCK) facilitates the storage of dietary TG fatty acids in WAT by regulating the activity of the LPL/ANGPTL-4 axis and that it does so by acting directly on CCK receptors in adipocytes. We report that administration of CCK-8 (a bioactive fragment of CCK) to rats: (i) reduces plasma ANGTPL-4 levels; (ii) represses Angptl-4 expression in WAT and (iii) simultaneously enhances LPL activity in this tissue without inducing Lpl expression. In vivo CCK-8 effects are specifically antagonized by the CCK-2 receptor (CCK-2R) antagonist, L-365,260. Moreover, CCK-8 downregulates Angptl-4 expression in wild-type pre-adipocytes, an effect that is not observed in engineered pre-adipocytes lacking CCK-2R. These effects have functional consequences as CCK-8 was found to promote the uptake of dietary fatty acids by WAT, as demonstrated by means of proton nuclear magnetic resonance (1H-NMR). The efficacy of acute CCK-8 administration was not reduced after chronic CCK-8 treatment. Moreover, the effects of CCK-8 on WAT were not associated to the increase of circulating insulin. Our results show that cholecystokinin promotes lipid storage in WAT by acting on adipocyte CCK-2R, suggesting a pivotal role for CCK in TG homeostasis.

Organ‐Specific Dietary Fatty Acid Uptake in Cold‐Acclimated Humans

In rodents, brown adipose tissue (BAT) plays an important role in producing heat to defend against the cold and in taking up and dissipating energy from dietary fat (Bartelt et al. Nat Med, 2011). Recent investigations have shown that BAT in humans can also contribute to cold‐induced thermogenesis, but its role in dietary fat metabolism remains unclear. Dietary fat may be responsible for the postprandial accretion of triglycerides in lean tissues in individuals with pre‐diabetes (Labbé SM et al. Diabetes, 2012; Kunach M et al. Diabetes 2015), which impairs insulin sensitivity. Thus, the contribution of BAT to postprandial thermogenesis and dietary fat metabolism warrants further clarification. We used our well‐established positron emission tomography (PET) method with oral administration of 18F‐fluoro‐thiaheptadecanoic acid (18FTHA) and i.v. 11C‐acetate to determine the effect of BAT metabolic activation on organ‐specific dietary fatty acid uptake and partitioning in humans. Non‐cold acclimated healthy men took part in 2 metabolic studies before and after a 4‐week cold acclimation, previously shown to increase BAT oxidative capacity (Blondin et al. JCEM, 2014). A standard liquid meal containing the fatty acid PET tracer 18FTHA was given at the beginning, while 11C‐acetate was given at time 60 min during a 4‐h acute cold exposure. Preliminary results show that fractional dietary fatty acid uptake was greater in BAT, compared to muscle or subcutaneous white adipose tissue (0.31±0.009 min−1 vs. 0.009±0.003 min−1 and 0.018±0.008 min−1, respectively). However, increasing BAT oxidative capacity 2.9‐fold, through daily cold exposure over 4 weeks, did not increase BAT uptake of dietary fatty acids any further (0.31±0.009 min−1 vs. 0.021±0.006 min−1). Dietary fatty acid partitioning was significantly lower in BAT than in the liver and heart (0.37±0.12 SUVmean vs. 2.18±0.53 SUVmean and 1.01±0.30 SUVmean, respectively), but comparable to the levels seen in abdominal subcutaneous white adipose tissues (0.17.±0.05 SUVmean) and skeletal muscles (0.17.±0.04 SUVmean). These findings show that although cold‐stimulated BAT can contribute minimally to the clearance of dietary fatty acids in humans, dietary fatty acids are not the primary source of energy for the chronic cold acclimation‐induced increase in BAT oxidative metabolism.Support or Funding InformationThis research was supported by the Canadian Institutes of Health Research (OG‐3‐10‐2970‐AC) and the Natural Sciences and Engineering Research Council of Canada (RGPIN/326967‐2011).

Seven-Day Caloric and Saturated Fat Restriction Increases Myocardial Dietary Fatty Acid Partitioning in Impaired Glucose-Tolerant Subjects.

Subjects with impaired glucose tolerance (IGT) have increased myocardial partitioning of dietary fatty acids (DFAs) with left ventricular dysfunction, both of which are improved by modest weight loss over 1 year induced by lifestyle changes. Here, we determined the effects of a 7-day hypocaloric diet (-500 kcal/day) low in saturated fat (<7% of energy) (LOWCAL study) versus isocaloric with the usual amount saturated fat (∼10% of energy) diet (ISOCAL) on DFA metabolism in subjects with IGT. Organ-specific DFA partitioning and cardiac and hepatic DFA fractional uptake rates were measured in 15 IGT subjects (7 males/8 females) using the oral 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid positron emission tomography method after 7 days of an ISOCAL diet versus a LOWCAL diet using a randomized crossover design. The LOWCAL diet led to reductions in weight and postprandial insulin area under the curve. Myocardial DFA partitioning over 6 h was increased after the LOWCAL diet (2.3 ± 0.1 vs. 1.9 ± 0.2 mean standard uptake value, P < 0.04). However, the early (90-120 min) myocardial DFA fractional uptake was unchanged after the LOWCAL diet (0.055 ± 0.025 vs. 0.046 ± 0.009 min(-1), P = 0.7). Liver DFA partitioning was unchanged, but liver fractional uptake of DFA tended to be increased. Very short-term caloric and saturated fat dietary restrictions do not lead to the same changes in organ-specific DFA metabolism as those associated with weight loss in subjects with IGT.

Effect of Sex and Impaired Glucose Tolerance on Organ-Specific Dietary Fatty Acid Metabolism in Humans.

Oral 14(R,S)-[(18)F]-fluoro-6-thia-heptadecanoic acid was used to determine whether an increase in cardiac dietary fatty acid (DFA) metabolism in impaired glucose tolerance (IGT) is different in men and women. Myocardial DFA partitioning after 6 h was higher in IGT versus control subjects (P = 0.006) in both men (2.14 [95% CI 1.70-2.18] vs. 1.28 standard uptake value [SUV] units [0.80-1.76]) and women (1.95 [1.57-2.33] vs. 1.64 SUV units [1.32-1.96]) without difference between sexes. Myocardial DFA fractional uptake (Ki) between time 90 and 120 min postprandially was also higher in IGT versus control subjects (P < 0.001) in men (0.063 [0.032-0.095] vs. 0.016 min(-1) [0.007-0.025]) and women (0.050 [0.024-0.077] vs. 0.030 min(-1) [0.013-0.047]) without significant sex difference. Men had higher net myocardial DFA uptake between time 90 and 120 min driven by higher chylomicron-triglyceride (TG) levels. IGT-associated increased cardiac DFA partitioning was directly related to obesity in women, whereas it was associated with IGT per se in men. We conclude that early cardiac DFA uptake is higher in men driven by change in postprandial chylomicron-TG level but that increase in 6-h postprandial cardiac DFA partitioning nevertheless occurs with IGT both in men and women.

Increased Myocardial Uptake of Dietary Fatty Acids Linked to Cardiac Dysfunction in Glucose-Intolerant Humans

Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGT+) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGT−). Measured by [11C]acetate with PET, IGT+ subjects have a significant increase in myocardial oxidative index. IGT+ subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT+ directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT+ versus IGT−. The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism.

The Impact of Membrane Lipid Composition on Macrophage Activation in the Immune Defense against Rhodococcus equi and Pseudomonas aeruginosa

Nutritional fatty acids are known to have an impact on membrane lipid composition of body cells, including cells of the immune system, thus providing a link between dietary fatty acid uptake, inflammation and immunity. In this study we reveal the significance of macrophage membrane lipid composition on gene expression and cytokine synthesis thereby highlighting signal transduction processes, macrophage activation as well as macrophage defense mechanisms. Using RAW264.7 macrophages as a model system, we identified polyunsaturated fatty acids (PUFA) of both the n-3 and the n-6 family to down-regulate the synthesis of: (i) the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α; (ii) the co-stimulatory molecule CD86; as well as (iii) the antimicrobial polypeptide lysozyme. The action of the fatty acids partially depended on the activation status of the macrophages. It is particularly important to note that the anti-inflammatory action of the PUFA could also be seen in case of infection of RAW264.7 with viable microorganisms of the genera R. equi and P. aeruginosa. In summary, our data provide strong evidence that PUFA from both the n-3 and the n-6 family down-regulate inflammation processes in context of chronic infections caused by persistent pathogens.

Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography

A noninvasive method to determine postprandial fatty acid tissue partition may elucidate the link between excess dietary fat and type 2 diabetes. We hypothesized that the positron-emitting fatty acid analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered (18)FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant (18)FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of (18)FTHA in the distal thoracic duct, reaching a peak at time 240 min. (18)FTHA mean standard uptake value increased progressively in the liver, heart, quadriceps, and subcutaneous and visceral adipose tissues between time 60 and 240 min. Most circulating (18)F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received (18)FTHA by gavage, we confirmed that >90% of this tracer reached the circulation as triglycerides. This novel noninvasive method to determine tissue dietary fatty acid distribution in humans should prove useful in the study of the mechanisms leading to lipotoxicity.

Silencing of Hepatic Fatty Acid Transporter Protein 5 in Vivo Reverses Diet-induced Non-alcoholic Fatty Liver Disease and Improves Hyperglycemia

Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease.

Obesity and Atherogenic Dyslipidemia

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.